Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy

Abstract

Objectives: To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy.

Background: CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants.

Results: We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10).

Discussion: Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.

Figure. Pedigrees and Genetic and Radiologic Findings of the Patients

(A) Pedigree of families 1–12. In the pedigree, squares represent men; circles represent women; black-shaded symbols denote affected patients harboring monoallelic CHD2 variants; and plus (+) and minus (−) signs indicate presence or absence of the CHD2 variants ([+/−] heterozygote and [−/−] wild type). (B) Schematic depiction of full-length CHD2 shows 2 chromodomains (pink), a helicase ATP-binding domain (green), and a helicase C-terminal domain (light blue). Variants identified in this cohort are displayed in bold and red. (C) The HomoloGene-generated amino acid alignment of human CHD2 and its predicted orthologs show the conservation of the amino acids Thr645, Gly871, Arg903, Arg1038, and Gly1575. (D) Brain MRI scans of Patient 1 performed at 13 years of age (a), Patient 2 at 3 years (b), Patient 4 at 8 years (c), Patient 6 at 7 years (d), Patient 7 at 11 years (e), Patient 8 at 7 years (f), Patient 11 at 11 years (g), Patient 14 at 5 years (h), Patient 15 at 4.5 years (i), and Patient 7 at 7 years of age (j). Coronal FLAIR or T2-weighted or IR images at the level of the hippocampi demonstrate unilateral or bilateral incomplete hippocampal rotation in Patients 1, 2, and 4 (thick arrows in a, b, and c). There is bilateral T2 or FLAIR hyperintensity of the hippocampi in Patients 4, 7, 8, and 11 (dashed arrows in c, e, f, and g). Additional mild hippocampal volume loss is noted in Patients 4 and 7.